Tag: Lung Cancer: Non-Small Cell

Osimertinib Plus Chemotherapy Superior to Osimertinib Alone in Advanced EGFR Mutated Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. Approximately 25% of patients with EGFR mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than eight months. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.

Osimertinib (TAGRISSO®) is a highly selective third-generation, irreversible Epidermal Growth Factor Receptor TKI, presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Further, Osimertinib has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases.

In the Phase III FLAURA trial, among patients with metastatic, EGFR-mutant NSCLC, first-line treatment with Osimertinib significantly improved median Overall Survival, compared with Erlotinib and Gefitinib, and should therefore has been the preferred regimen in this patient group. The FLAURA2 trial builds on the favorable results observed in the Phase III FLAURA trial.

FLAURA2 is a randomized, open-label, multi-center, global, ongoing Phase III trial, in which 557 enrolled treatment naïve patients (N=557) with nonsquamous locally advanced (Stage IIIB-IIIC) or metastatic EGFR mutated NSCLC were randomly assigned 1:1 to receive Osimertinib plus chemotherapy (N=279) or Osimertinib monotherapy (N=278). Patients in the combination group received Osimertinib 80 mg oral tablets once daily in combination with chemotherapy consisting of Pemetrexed 500 mg/m2 IV plus Cisplatin 75 mg/m2 IV or Carboplatin (AUC5), every three weeks for four cycles, followed by Osimertinib with Pemetrexed maintenance every three weeks. The median patient age was 62 years, approximately 62% were women and 64% were Asian. Approximately 76% of patients completed four cycles of platinum therapy. The Primary end point was investigator-assessed Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and Safety.

In this final analysis of the Primary endpoint of PFS, results from this study showed a significant improvement in Progression Free Survival (PFS) with the Osimertinib plus chemotherapy combination versus Osimertinib alone, with an 8.8-month improvement in median PFS with the combination regimen (HR=0.62; P<0.0001). This represented a 38% reduction in disease progression risk, compared to Osimertinib monotherapy. In addition, median PFS determined by blinded Independent Central Review showed a 9.5-month improvement with the combination regimen. The Objective Response Rate with the combination regimen was 83%, compared to 76%, in the Osimertinib monotherapy group. Grade 3 or higher hematologic adverse events occurred more frequently in the combination regimen group and were manageable. Data for Overall Survival were immature at the time of the analysis, and this ongoing trial will continue to assess the Secondary endpoint of Overall Survival.

The authors concluded that FLAURA2 provides compelling evidence that the addition of chemotherapy to Osimertinib in the first line treatment of nonsquamous, locally advanced or metastatic EGFR mutated NSCLC, can further improves outcomes, compared to Osimertinib alone, and can delay resistance to therapy and disease progression.

FLAURA2 results demonstrate osimertinib plus chemotherapy superior compared to osimertinib alone (press release). Available at: https://www.iaslc.org/iaslc-news/press-release/flaura2-results-demonstrate-osimertinib-plus-chemotherapy-superior. Published Sept.10, 2023.

FDA Approves Pralsetinib for Non Small Cell Lung Cancer with RET gene fusions

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SUMMARY: The FDA on August 9, 2023, granted regular approval to Pralsetinib (GAVRETO®) for adult patients with metastatic Rearranged during Transfection (RET) fusion-positive Non-Small Cell Lung Cancer (NSCLC) as detected by an FDA approved test. Pralsetinib was previously granted accelerated approval for the NSCLC indication in Sept. 2020, based on initial Overall Response Rate (ORR) and Duration of Response (DOR) in 114 patients enrolled in the ARROW trial. The conversion to regular approval was based on data from an additional 123 patients and 25 months of additional follow up, to assess Durability of Response.

Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer accounts for approximately 85% of all lung cancers.

In addition to the well characterized gene fusions involving ALK and ROS1 in NSCLC, genetic alterations involving other kinases including EGFR, BRAF, RET, MET, KRAS, NTRK, are all additional established targetable drivers. These genetic alterations are generally mutually exclusive, with no more than one predominant driver in any given cancer. The hallmark of all of these genetic alterations is oncogene addiction, in which cancers are driven primarily, or even exclusively, by aberrant oncogene signaling, and are highly susceptible to small molecule inhibitors.

RET kinase is a transmembrane Receptor Tyrosine Kinase and plays an important role during the development and maintenance of a variety of tissues, including neural and genitourinary tissues. RET signaling activates downstream pathways such as JAK/STAT3 and RAS/RAF/MEK/ERK and leads to cellular proliferation, survival, invasion, and metastasis. Oncogenic alterations to the RET proto-oncogene results in uncontrolled cell growth and enhanced tumor invasiveness. RET alterations include RET rearrangements, leading to RET fusions, and activating point mutations occurring across multiple tumor types. RET fusions have been identified in approximately 2% of NSCLCs, 10-20% of non-medullary thyroid cancers. Activating RET point mutations account for approximately 60% of sporadic Medullary Thyroid Cancers (MTC) and more than 90% of inherited MTCs. Other cancers with documented RET alterations include colorectal, breast, and several hematologic malignancies.

Patients without a driver mutation are often treated with a platinum-doublet cytotoxic chemotherapy with/without Immune checkpoint inhibitors, or with Immune checkpoint inhibitor monotherapy. However, outcomes with immune checkpoint inhibitors remain poor in patients with RET fusion–positive NSCLC, regardless of PD-L1 expression.

Pralsetinib (GAVRETO®) is an oral, highly potent, selective RET kinase inhibitor targeting oncogenic RET alterations, including fusions and mutations, regardless of the tissue of origin. The efficacy of Pralsetinib was investigated in a multicenter, open-label, multi-cohort, Phase I/II basket clinical trial (ARROW), in patients with tumors showing RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either, Next Generation Sequencing (NGS), Fluorescence In Situ Hybridization (FISH), or other tests. (In a basket trial, tumors with different histologies and single biomarker are placed in different baskets and receive a single treatment). Phase I Pralsetinib dose escalation study determined 400 mg QD as the recommended Phase II trial dose. Phase II trial evaluated Pralsetinib in multiple expansion groups, defined by disease type and treatment history.

The FDA regular approval was based on the efficacy of Pralsetinib in a total of 237 patients (N=237) with locally advanced or metastatic RET fusion-positive NSCLC. Patients received Pralsetinib 400 mg once daily until disease progression or unacceptable toxicity. Among the patients studied, 107 (N=107) were treatment-naïve and 130 patients (N=130) were previously treated with platinum-based chemotherapy. The main efficacy outcome measures were Overall Response Rate (ORR) and Duration of Response, as determined by a Blinded Independent Review Committee, using RECIST criteria.

The median age of the 107 patients in the treatment-naïve group was 63 years and 28% of patients had a history of or active CNS/brain metastases. The ORR in this group was 78%, with a Complete Response (CR) rate of 7%. The median Duration of Response was 13.4 months and 45% of patients experienced a Duration of Response of 12 months or longer.

The median age of the 130 patients in the group that was previously treated with platinum-based chemotherapy, was 59 years and 41% had a history of or active CNS/brain metastases. The ORR in this group was 63% with a CR rate of 6%. The median Duration of Response of 38.8 months and 66% of patients experienced a Duration of Response of at least 12 months.

In patients with measurable intracranial metastases, the intracranial response rate was 70%.

The most common adverse reactions were fever, fatigue, cough, constipation, diarrhea, musculoskeletal pain, hypertension and edema.

It was concluded from this study that treatment with Pralsetinib produced robust efficacy including intracranial activity, in patients with advanced RET fusion–positive NSCLC who are treatment-naive or are refractory to standard-of-care chemotherapy. Results from the confirmatory Phase III AcceleRET Lung study of Pralsetinib versus standard of care in the first-line setting are eagerly awaited and may further support the use of Pralsetinib for RET fusion-positive NSCLC in the first-line setting.

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pralsetinib-non-small-cell-lung-cancer-ret-gene-fusions

Perioperative Pembrolizumab for Early Stage Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2.

KEYNOTE-671 trial is a randomized, double-blind, placebo-controlled, Phase III trial, conducted to evaluate whether a perioperative approach of combined neoadjuvant Pembrolizumab plus Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, would improve efficacy as compared with neoadjuvant Cisplatin-based chemotherapy and resection alone, in patients with resectable Stage II or III NSCLC. This study included patients with pathologically confirmed, resectable Stage II, IIIA, or IIIB (N2 disease-with involvement of 1 or more ipsilateral mediastinal lymph nodes or subcarinal lymph node) NSCLC. Eligible patients were randomly assigned in a 1:1 ratio to receive neoadjuvant Pembrolizumab 200 mg IV (N=397) or placebo (N=400) once every 3 weeks, each of which was given with Cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant Pembrolizumab 200 mg IV or placebo once every 3 weeks for up to 13 cycles. The median age was 64 years, 70% had Stage III disease, about 44% had N2 nodal stage, 57% has nonsquamous histology and 43% had squamous histology, about 36% had less than 1% PD-L1 Tumor Proportion Score (TPS), whereas 30% of patients had tumors with a TPS of 1-49% and 33% had TPS of 50% or more. The dual Primary end points were Event-Free Survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death), and Overall Survival. Secondary end points included major pathological response, Pathological Complete Response, and Safety.

The researchers reported the efficacy and safety data from the prespecified first interim analysis. The median follow-up was 25.2 months. Event-Free Survival at 24 months was 62.4% in the Pembrolizumab group and 40.6% in the placebo group (HR=0.58; P<0.001). The estimated 24-month Overall Survival was 80.9% in the Pembrolizumab group and 77.6% in the placebo group and this was not statistically significant (P=0.02). A major pathological response occurred in 30.2% of the patients in the Pembrolizumab group and in 11.0% of those in the placebo group (P<0.0001) and a pathological Complete Response occurred in 18.1% and 4.0%, respectively (P<0.0001). An exploratory analysis showed that the Event-Free Survival benefit was noted in the Pembrolizumab group regardless of whether participants had a major pathological response or a pathological Complete Response. The benefit with Pembrolizumab therapy appeared to be similar across both squamous and nonsquamous histologies. Approximately 45% of the patients in the Pembrolizumab group and 37% in the placebo group had treatment-related adverse events of Grade 3 or higher.

It was concluded that among patients with resectable Stage II, IIIA, or IIIB (N2 stage) NSCLC, the addition of Pembrolizumab to neoadjuvant Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, led to a significant improvement in Event-Free Survival, major pathological response, and Pathological Complete Response, as compared with neoadjuvant chemotherapy alone followed by surgery. It should be noted that this trial was not designed to assess the relative contribution of adjuvant Pembrolizumab.

Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. Wakelee H, Liberman M, Kato T, et al., for the KEYNOTE-671 Investigators. N Engl J Med 2023;389:491-503.

Late Breaking Abstract – ASCO 2023: Tumor Treating Fields Plus Standard of Care Improves Overall Survival in Patients with Metastatic Non-Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Tumor Treating Fields (TTFields) delivery system is a non-invasive novel external therapeutic device that slows and reverses tumor growth by disrupting mitosis. The battery operated portable at-home TTF delivery system generates low intensity, intermediate frequency, alternating electrical fields delivered locoregionally to the tumors through 2 pairs of arrays applied to the chest. These electrical fields exert selective toxicity in dividing cells by interfering with organelle assembly in the cell and thereby facilitates apoptosis (programmed cell death), by preventing cell division. The non-dividing cells are not affected by these electrical fields. Patients wear the device for at least 18 hours a day and for at least four weeks. Currently, TTF therapy is approved for Glioblastoma and Malignant Pleural Mesothelioma. Preclinical NSCLC studies have shown that TTFields enhance the antitumor immune response, through disruption of mitosis and subsequent induction of immunogenic cell death. Further, TTFields synergize with taxanes and Immune Checkpoint Inhibitors (ICIs). This was the rationale for the development and design of the LUNAR Phase III trial.

The LUNAR study is a global, randomized, Phase III trial in which the safety and efficacy of Tumor Treating Fields therapy with Standard of Care, was compared to Standard of Care alone, in patients with metastatic Non Small Cell Lung Cancer (NSCLC), who had progression on or after Platinum-based chemotherapy. In this study, 276 eligible patients (N=276) were randomized 1:1 to receive either Tumor Treating Fields therapy (150 kHz) plus Standard of Care, which included investigator’s choice of an Immune Checkpoint Inhibitor (ICI) or Docetaxel, or Standard of Care alone. To be eligible for this study, patients had to be 22 years or older, have metastatic NSCLC, should have progressed on or after a platinum-based therapy, and have an ECOG performance status of 0-2. Both treatment groups were well balanced. The median age was 64 years, 65% were male, 96% of patients had an ECOG PS of 0-1, 56% had non-squamous histology, 89% had one prior line of systemic therapy and 31% received prior therapy with ICI. Patients were followed every 6 weeks and continued on therapy until disease progression or intolerable toxicities. The Primary endpoint was Overall Survival (OS). Secondary endpoints included were OS in ICI and Docetaxel subgroups, Progression Free Survival (PFS) and toxicities.

This study met its Primary end point of Overall Survival and OS was significantly extended with Tumor Treating Fields therapy plus Standard of Care versus Standard of Care. After a minimum follow up of 12 months, the median Overall Survival with Tumor Treating Fields therapy plus Standard of Care was 13.2 months versus 10.0 months with Standard of Care alone (HR=0.74; P=0.037) and 1-year survival rates were 53% and 42% respectively (P=0.040). In patients receiving an Immune Checkpoint Inhibitor (N=134), the addition of Tumor Treating Fields therapy significantly improved median OS versus ICI alone (18.5 months versus 10.6 months; HR=0.63; P=0.032). In those patients treated with Docetaxel, the median OS was numerically higher at 11.1 months with Tumor Treating Fields therapy plus Docetaxel versus 8.9 months with Docetaxel alone (HR=0.87). There was no significant difference in the median PFS between the two treatment groups and were 4.8 months and 4.1 months respectively. The rate of Adverse Events was similar between the treatment groups and majority of the Tumor Treating Fields associated toxicities were Grade 1 and 2 local skin irritations.

The authors concluded that in this Phase III study, the addition of Tumor Treating Fields therapy to Standard of Care therapy significantly extended Overall Survival in patients with metastatic NSCLC following platinum failure, without increasing systemic toxicities, and Tumor Treating Fields therapy may be a potentially paradigm-shifting new treatment modality.

Tumor treating fields (TTFields) therapy with standard of care (SOC) in metastatic non-small cell lung cancer (mNSCLC) following platinum failure: Randomized phase 3 LUNAR study. Leal T, Kotecha R, Ramlau R, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA9005)

Late Breaking Abstract – ASCO 2023: Overall Survival with TAGRISSO® in Resected EGFR-Mutated NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. Approximately 25% of patients with EGFR mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than eight months. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.

TAGRISSO® (Osimertinib) is a highly selective third-generation Epidermal Growth Factor Receptor (EGFR) TKI presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Further, TAGRISSO® has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases. Among patients with metastatic, EGFR-mutant NSCLC, first-line treatment with TAGRISSO® significantly improved median Overall Survival, compared with TARCEVA® and IRESSA®, and should therefore be considered the preferred regimen.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

ADAURA is a global, double-blind, randomized Phase III study, which assessed the efficacy and safety of TAGRISSO® versus placebo in patients with Stage IB–IIIA EGFR mutated NSCLC, after complete tumor resection and adjuvant chemotherapy, when indicated. In this study, 682 patients with completely resected Stage IB, II, IIIA NSCLC, with or without postoperative adjuvant chemotherapy, were randomly assigned 1:1 to receive either TAGRISSO® 80 mg orally once daily (N=339) or placebo (N=343) once daily, for up to 3 years. Eligible patients had an ECOG Performance Status of 0 or 1, with confirmed EGFR mutations (Exon 19del or L858R). Treatment groups were well balanced and patients were stratified by Stage (IB/II/IIIA), mutation type (Exon 19del/L858R), and race (Asian/non-Asian). Most patients with Stage II to IIIA disease (76%) and approximately a quarter of the patients with Stage IB disease (26%) received adjuvant platinum-based chemotherapy. The Primary endpoint was Disease Free Survival (DFS) in Stage II–IIIA patients. Secondary endpoints included DFS in the overall population of patients with Stage IB to IIIA disease, Overall Survival (OS) and Safety. Following Independent Data Monitoring Committee recommendation, the trial was unblinded early, due to efficacy.

The FDA approved TAGRISSO® for use as adjuvant treatment in late 2020 based on the primary analysis data demonstrating that in the patients with Stage II/IIIA disease, the DFS had not been reached with TAGRISSO® versus 19.6 months with placebo (HR=0.17; P<0.001). This was equal to an 83% reduction in the risk of recurrence or death, indicating a significantly longer DFS among patients in the TAGRISSO® group, compared to those in the placebo group. The 2-year DFS rate in this patient group with TAGRISSO® was 90% versus 44% with placebo. In the overall population, which included Stage IB to IIIA disease, the median DFS was not reached with TAGRISSO® versus 27.5 months with placebo (HR=0.20; P<0.001). This Hazard Ratio equaled to an 80% reduction in the risk of disease recurrence or death among patients in the TAGRISSO® group compared to those in the placebo group. The 2-year DFS rate in the overall population was 89% with TAGRISSO® versus 52% with placebo. Updated data presented at the 2022 ESMO Congress showed that at a median follow up of 44.2 months, the DFS with TAGRISSO® was still robust at 77% in patients with Stage II/IIIA disease and 73% in the overall Stage IB-IIIA population.

The researchers herein reported the planned final Overall Survival (OS) analysis from ADAURA. Adjuvant TAGRISSO® significantly improved OS compared to placebo and reduced the risk of death by 51% compared to placebo in both Stages II-IIIA (HR for OS=0.49; P=0.0004), and in the overall Stages IB-IIIA trial population (HR=0.49; P<0.0001). This survival benefits with TAGRISSO® was seen, regardless of whether prior adjuvant chemotherapy was received. The 5-year OS rate was 88% in the TAGRISSO® group and 78% in the placebo group. Median OS was not reached in either population or treatment group. The safety profile with adjuvant TAGRISSO® was consistent with that in the primary analysis.

It was concluded that adjuvant TAGRISSO® demonstrated an unprecedented, highly statistically significant and clinically meaningful Overall Survival benefit in patients with EGFR mutated Stage IB–IIIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy. The authors added that ADAURA is the first global Phase III study to demonstrate a statistically significant Disease Free Survival and Overall Survival benefit with targeted treatment for this patient group, reinforcing the importance of testing for biomarkers at the time of diagnosis and before starting therapy.

Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. Tsuboi M, Herbst RS, John T, et al., for the ADAURA Investigators. June 4, 2023. DOI: 10.1056/NEJMoa2304594

Association between Duration of Immunotherapy and Overall Survival in Advanced Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL‐derived Interferon‐γ, Neutrophil‐to‐Lymphocyte ratio, and peripheral cytokines, have also been proposed as predictors of response.

The optimal duration of treatment with ICIs across tumor types is currently unknown and finding the balance between efficacy, toxicity and cost of therapy remains an ongoing challenge. There are presently no adequately powered, prospective, ICI trials, comparing different treatment durations. Even though patients were treated with first line ICI therapy for up to 2 years in key pivotal trials, a significant number of clinicians are hesitant to discontinue ICI therapy and many patients continue therapy beyond 2 years.
The present study was conducted to assess practice patterns surrounding ICI treatment discontinuation at 2 years and to evaluate the association of duration of therapy with Overall Survival, in patients who received Fixed-Duration ICI therapy for 2 years versus those who continued therapy beyond 2 years.

The researchers in this retrospective, population-based cohort study used the longitudinal Flatiron Health database derived from the Electronic Health Record, which included deidentified data of patients originating from approximately 280 cancer clinics (approximately 800 sites of care) throughout the US. The present study cohort included 1091 adult patients (aged at least 18 years) with a new diagnosis of advanced or metastatic NSCLC between 2016 and 2021, who received frontline treatment with Immune Checkpoint Inhibitor (ICI) either alone or in combination with chemotherapy, who were still on ICI treatment at 2 years, and whose cancer had not progressed. Patients with driver mutations in EGFR, ALK, or ROS1 were excluded. Of these patients who initiated treatment with first-line immunotherapy, the researchers focused on 706 patients who completed 2 years of therapy with ICI, of whom 113 patients stopped ICI therapy at 2 years (Fixed-Duration Therapy group) and 593 patients continued ICI therapy beyond 2 years (Indefinite-Duration Therapy group). The median age was 69 years in both treatment groups Patients in the Fixed-Duration group versus the Indefinite-Duration group were more likely to have a history of smoking, respectively and be treated in an academic center. Approximately 50% of patients in both groups were treated initially with immunotherapy alone versus chemoimmunotherapy. The researchers compared the survival between long-term ICI responders whose therapy was discontinued at 2 years in the absence of death or progression (Fixed-Duration group) and those who continued ICI beyond 2 years (Indefinite-Duration group).

With a median follow up of 14.0 months starting 760 days after treatment initiation, there was no statistically significant difference in Overall Survival between patients treated with Fixed-Duration and Indefinite-Duration ICI therapy on either unadjusted or adjusted analysis, and was 79% and 81% respectively. The researchers noted that among patients still on ICI treatment at 2 years, 4 out of 5 patients continued to receive immunotherapy rather than discontinuing it, suggesting that there was a strong bias toward potential overtreatment versus possible undertreatment.

A small cohort of patients in the Fixed-Duration therapy group had disease progression, and was rechallenged with ICI after at least 30 days without treatment. The median time from cessation of frontline treatment to initiation of second-line therapy was 7.4 months. After ICI rechallenge, median Progression Free Survival 2 (PFS2) was 8.1 months.

The authors from this study findings concluded that for patients who are progression-free on Immune Checkpoint Inhibitor therapy for NSCLC, it is a reasonable strategy to stop ICI therapy at 2 years, rather than continuing therapy indefinitely, as there was no statistically significant difference in Overall Survival by Fixed-Duration (2 years) versus Indefinite-Duration (more than 2 years) of ICI therapy.

Association Between Duration of Immunotherapy and Overall Survival in Advanced Non–Small Cell Lung Cancer. Sun L, Bleiberg B, Hwang W-T, et al. JAMA Oncol. Published online June 4, 2023. doi:10.1001/jamaoncol.2023.1891

Treatment of Oligometastatic Non-Small Cell Lung Cancer: An ASTRO/ESTRO Clinical Practice Guideline

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SUMMARY: The American Society for Radiation Oncology (ASTRO) and European Society for Radiotherapy and Oncology (ESTRO) convened a task force to review evidence and provide recommendations on the use of local therapy in the management of extracranial oligometastatic Non Small Cell Lung Cancer (NSCLC). Local therapy is defined as definitive comprehensive treatment of all known cancer (primary tumor, regional nodal metastases, and metastases). This joint guideline by ASTRO and ESTRO addressed 5 important questions focused on the use of local (radiation, surgery, other ablative methods) and systemic therapy in the management of oligometastatic NSCLC. The questions addressed clinical scenarios for using local therapy, sequencing and timing when integrating local with systemic therapies, radiation techniques critical for oligometastatic disease targeting and treatment delivery, and the role of local therapy for oligoprogression or recurrent disease.

Oligorecurrence refers to the general growth of limited numbers of metastatic deposits in patients off systemic therapy. For patients with oligometastates receiving active systemic treatment, they are considered as having oligoprogressive disease if current imaging establishes progression of disease in a limited number of existing and/or new sites, and oligopersistent disease if current imaging establishes stable disease or partial response to therapy, of the existing limited disease. The following recommendations were based on a systematic literature review, and created using ASTRO guidelines methodology. These recommendations focus on the management of extracranial disease with local therapy. This guideline and its recommendations with respect to the multimodally treatment strategy do not differentiate between patients with and without brain metastases.

Key Questions and Recommendations
What are the optimal patient/disease characteristics to select patients with oligometastatic NSCLC for definitive treatment combining systemic and local therapies?
1. Treatment decisions should be made using a patient-centered multidisciplinary team approach.
2. The integration of definitive local therapy is only recommended if technically feasible and clinically safe for all disease sites.
3. A discussion of definitive local therapy as a component of multimodality treatment approach is recommended irrespective of presence of activating driver mutations.
4. Definitive local therapy is recommended only for patients having up to 5 distant metastases, diagnosed with appropriate imaging. Implementation remark: Despite some prospective trials including patients with up to 5 extracranial metastases, most patients enrolled had 1-2 treated oligometastatic lesions, which should be factored into decision-making.
5. For patients with synchronous oligometastatic NSCLC, definitive local therapy to all cancer sites in addition to standard of care systemic therapy is conditionally recommended.
6. For patients with metachronous oligorecurrent NSCLC, definitive local therapy to all oligorecurrent cancer sites in addition to standard of care systemic therapy is conditionally recommended.
7. For patients with induced oligopersistent NSCLC, definitive local therapy to all persistent cancer sites in addition to standard of care systemic therapy is conditionally recommended.
8. For patients with induced oligoprogressive NSCLC receiving systemic therapy, definitive local therapy to all progressive cancer sites is conditionally recommended while continuing the current line of systemic therapy.

What are the selection criteria for choice of local treatment modality in the management of patients with oligometastatic NSCLC?
1. A patient-centered multidisciplinary discussion of the most appropriate local treatment strategy of RT and/or surgery, either alone or in combination, is recommended.
2. RT and/or surgery are recommended as definitive local treatment modalities for the locoregional primary and all oligometastases.
3. Highly conformal RT approaches and minimally invasive techniques for surgery are recommended to minimize morbidity.
4. Deciding between RT and surgery as the definitive local treatment modality should a) Favor RT when multiple organ systems are being treated b) Favor RT when the clinical prioritization is to minimize breaks from systemic therapy c) Favor surgery when large tissue sampling is needed for molecular testing, to guide systemic therapy.

What are the appropriate sequencing and timing of systemic therapy and definitive local therapies for patients with oligometastatic NSCLC?
1. For patients with synchronous oligometastatic NSCLC, 3 months or more of systemic therapy is recommended prior to definitive local therapy.
2. For patients with oligometastatic NSCLC, up-front definitive local treatment for symptomatic lesions should be prioritized. Implementation remark: Symptomatic disease sites (eg, brain metastases) are treated with up-front definitive local therapy.
3. For patients with synchronous oligometastatic NSCLC, the temporary pause of systemic therapy during definitive local therapy versus concomitant treatment should be discussed using a multidisciplinary team approach.
4. For patients with synchronous oligometastatic NSCLC, maintenance systemic therapy is conditionally recommended after completion of definitive local therapy.

What are the optimal dose-fractionation regimens, planning, and delivery technique of RT for patients with oligometastatic NSCLC?
1. Appropriate staging with FDG PET, cranial MRI, and MRI in cases of suspect or proven spine or liver metastases are recommended.
2. Individual assessment of respiratory motion for targets in the lungs and upper abdomen using 4-D CT, fluoroscopy, or MR-cine with appropriate motion compensation is recommended.
3. Highly conformal RT using inverse dose planning, appropriate motion management strategies and image-guided RT delivery are recommended.
4. A risk adapted approach using stereotactic RT (preferred), hypofractionated RT, or alternatively definitive chemoradiation based on the location and burden of disease is recommended.
5. Definitive local RT should use doses and fractionations which achieve durable local control.
Implementation remarks: a) Durable local control defined as minimum 85% local control at 2 years b) Higher BED10 (typically >75 Gy) with SBRT alone is associated with optimal local control c) Lower BED10 (50-75 Gy range) is associated with acceptable local control, typically in the setting of combination systemic therapy and SBRT.

After a definitive local therapy approach for oligometastatic NSCLC, what are the indications for additional local therapy upon disease progression?
1. Systemic therapy is recommended as the preferred treatment option.
2. Additional local therapy should be discussed using a multidisciplinary team approach.
3. Local therapy is conditionally recommended.
4. In patients previously treated with definitive local therapy for oligometastatic NSCLC who subsequently develop repeat oligoprogression or recurrence at sites previously treated with local therapy, re-treatment is conditionally recommended if systemic treatment options are limited, and local therapy can be delivered with toxicity acceptable to the multidisciplinary team and patient.

Treatment of Oligometastatic Non-Small Cell Lung Cancer: An ASTRO/ESTRO Clinical Practice Guideline. Iyengar P, All S, Berry MF, et al. Published:April 25, 2023. https://doi.org/10.1016/j.prro.2023.04.004

Tremelimumab in Combination with Durvalumab and Chemotherapy in Metastatic Non Small Cell Lung Cancer: The Phase III POSEIDON Study

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

IMFINZI® (Durvalumab) is a human immunoglobulin G1 monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics, and unleashes the T cells. IMJUDO® (Tremelimumab) is a human immunoglobulin G2 monoclonal antibody that targets and blocks the activity of CTLA-4, enhancing binding of CD80 and CD86 to CD28. This complimentary mechanisms of action broadens clinical activity, potentially overcoming primary resistance to PD-(L)1 blockade by enabling novel T-cell responses. The concurrent addition of chemotherapy to checkpoint inhibitors causes tumor cell death and release of neoantigens, which increases immune priming, important for early disease control.

POSEIDON is a global, randomized, open-label, three-arm, Phase III study, which evaluated the efficacy of Tremelimumab plus Durvalumab along with chemotherapy, and Durvalumab along with chemotherapy, compared to chemotherapy alone, in first-line treatment of metastatic NSCLC. In this trial, 1013 patients (N=1013) with EGFR/ALK wild-type metastatic NSCLC were randomly assigned (1:1:1) to receive either Tremelimumab 75 mg IV plus Durvalumab 1,500 mg IV along with chemotherapy for up to four 21-day cycles, followed by Durvalumab 1500 mg IV once every 4 weeks until disease progression, with one additional Tremelimumab dose after chemotherapy at week 16 (fifth dose), Durvalumab 1500 mg IV plus chemotherapy for up to four 21-day cycles, followed by Durvalumab 1500 mg IV once every 4 weeks until disease progression, or chemotherapy alone for up to six 21-day cycles. Chemotherapy options for treatment groups included Carboplatin plus nab-Paclitaxel regardless of histology, Cisplatin or Carboplatin plus Gemcitabine for patients with squamous histology, and Cisplatin or Carboplatin plus Pemetrexed for patients with nonsquamous histology. Patients with nonsquamous histology who received Pemetrexed-Platinum doublet could receive Pemetrexed maintenance therapy if eligible. Patients continued treatment until progressive disease or unacceptable toxicity. Patients were stratified by PD-L1 expression (50% or more versus less than 50%), disease Stage (IVA versus IVB), and histology (squamous versus nonsquamous). The median age was 64 yrs, 63% had nonsquamous histology, and approximately a third of the patients had PD-L1 expression less than 1%. The treatment groups were well balanced. The Primary end points were Progression Free Survival (PFS) and Overall Survival (OS) for the Durvalumab plus chemotherapy group, compared to the chemotherapy alone group. Key Secondary end points were PFS and OS for Tremelimumab plus Durvalumab along with chemotherapy, compared to chemotherapy alone.

The coPrimary end point of PFS benefit with Durvalumab plus chemotherapy compared to chemotherapy alone was met (HR=0.74; P=0.0009), and the median PFS was 5.5 versus 4.8 months respectively and the 12-month PFS rates were 24.4% versus 13.1%. However, OS did not reach statistical significance (HR=0.86; P=0.075). When Secondary end points were formally evaluated, Tremelimumab plus Durvalumab and platinum-based chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS compared to chemotherapy alone (HR=0.77; P=0.003). The median OS was 14 months versus 11.7 months respectively and 2 year OS was 32.9% versus 22.1% respectively. The median PFS was 6.2 months and 4.8 months in the treatment arms, respectively (HR=0.72; P=0.0003) and the 1-year PFS rate was 26.6% and 13.1% respectively. Treatment benefit was seen across all PD-L1 subgroups, particularly in tumors with PD-L1 expression of 50% or more. Patients with tumor PD-L1 expression less than 1% appeared to gain improved survival benefit from the addition of Tremelimumab to Durvalumab and chemotherapy.

Based on this study, the FDA approved Tremelimumab in combination with Durvalumab and platinum-based chemotherapy for adult patients with metastatic NSCLC, with no sensitizing EGFR mutation or ALK genomic tumor aberrations.

It was concluded that Durvalumab plus chemotherapy significantly improved Progression Free Survival when compared to chemotherapy alone. A limited course of Tremelimumab added to Durvalumab and chemotherapy significantly improved Overall Survival and Progression Free Survival when compared to chemotherapy, and the clinical benefit extended to patients who had tumor PD-L1 expression less than 1%.

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study. Johnson ML, Cho BC, Luft A, et al. DOI: 10.1200/JCO.22.01737 Journal of Clinical Oncology 41, no. 6 (February 20, 2023) 1176-1179.

Five Year Outcomes with KEYTRUDA® Plus Chemotherapy in Metastatic Nonsquamous Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

KEYTRUDA® is a fully humanized, immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced NSCLC have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-189 is a double-blind, Phase III trial in which 616 patients with untreated Stage IV non-squamous NSCLC, without sensitizing EGFR or ALK mutations, were randomly assigned in a 2:1 ratio to receive treatment with four cycles of KEYTRUDA®/Pemetrexed/Carboplatin (N=410) or placebo plus the same chemotherapy (N=206). Patients then received either KEYTRUDA® 200 mg or saline placebo, both administered IV every 3 weeks for up to 35 cycles. All the patients received four cycles of the investigator’s choice of Cisplatin 75 mg/m2 IV or Carboplatin AUC 5 along with Pemetrexed 500 mg/m2, all administered IV every 3 weeks, followed by maintenance Pemetrexed 500 mg/m2 every 3 weeks. Patients in the placebo combination group were allowed to crossover to KEYTRUDA® monotherapy upon disease progression. Patients with symptomatic brain metastasis were excluded and patients were stratified according to PD-L1 expression (Tumor Proportion Score, 1% or more versus less than 1%), choice of platinum-based drug (Cisplatin versus Carboplatin), and smoking history. Both treatment groups were well balanced and about 17% had brain metastasis and one-third were untreated. A PD-L1 Tumor Proportion Score of 1% or more was reported in 63% of the patients, Carboplatin was the preferred platinum-based drug in 72% of the patients, and 88% of the patients were current or former smokers. The co-Primary end points were Overall Survival (OS) and Progression Free Survival (PFS). Secondary end points included Objective Response Rate (ORR) and Duration of Response (DOR) and Safety. Exploratory end points included PFS2 (time from random assignment to second/subsequent progressive disease on next-line treatment or death from any cause).

In the initial report from the trial, after a median follow-up of 10.5 months, the median PFS was 8.8 months in the KEYTRUDA® combination group and 4.9 months in the placebo combination group (HR=0.52; P<0.001) and the median OS was Not Reached with KEYTRUDA® combination and was 11.3 months in the placebo combination group (HR=0.49; P<0.001).

In this updated analysis, the researchers presented 5-year outcomes from the Phase III KEYNOTE-189 study. The median time from randomization to data cutoff (in March 2022) was 64.6 months. There was continued benefit in the Progression Free Survival and Overall Survival in the KEYTRUDA® group compared to the control group (HR=0.50 versus HR=0.60, respectively). The 5-year Progression Free Survival rates were 7.5% versus 0.6% and 5-year Overall Survival rates were 19.4% versus 11.3% respectively. The Objective Response Rate in the KEYTRUDA® group was 48.3% versus 19.9% in the control group, and the median Duration of Response was 12.7 and 7.1 months, respectively. Similar trends were observed across the PD-L1 subgroups analyzed. Among the 57 patients assigned to KEYTRUDA® combination and completed 35 cycles of KEYTRUDA®, the Objective Response Rate was 86% and the estimated Overall Survival rate 3 years after completion of 35 cycles (approximately 5 years from random assignment) was 71.9%. Sustained improvements in Overall Survival were observed in the KEYTRUDA® combination group, despite a crossover rate of 57% of patients from placebo plus chemotherapy to subsequent anti-PD1 therapy, further supporting the use of KEYTRUDA® plus chemotherapy as first-line treatment.

It was concluded that KEYTRUDA® in combination with Pemetrexed and Platinum chemotherapy continued to demonstrate prolonged survival and durable antitumor activity, compared to chemotherapy alone, regardless of PD-L1 expression. The authors added that these data continue to support the combination of first-line KEYTRUDA® plus a Platinum and Pemetrexed as a standard of care, in patients with previously untreated metastatic nonsquamous NSCLC, without EGFR/ALK alterations.

Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. Garassino MC, Gadgeel S, Speranza G, et al. DOI: 10.1200/JCO.22.01989 Journal of Clinical Oncology. Published online February 21, 2023.